Download Repolarization reserve, arrhythmia and new drug development

Acta Pharmaceutica Sinica B 2013;3(3):150–153
Institute of Materia Medica, Chinese Academy of Medical Sciences
Chinese Pharmaceutical Association
Acta Pharmaceutica Sinica B
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REVIEW
Repolarization reserve, arrhythmia and new
drug development
Yang Lin, Yicheng Fu
Institute of Geriatric Cardiology, the Chinese PLA General Hospital, Beijing 100853, China
Received 25 December 2012; revised 15 February 2013; accepted 22 February 2013
KEY WORDS
Repolarization reserve;
Ion channels;
Arrhythmias;
QT prolongation;
Drug development
strategy
Abstract Repolarization-related lethal arrhythmias have led to the concept of “repolarization reserve”,
which may help elucidate the relationship between Kþ currents and other components of repolarization.
Pharmacological manipulation as well as congenital and cardiac disease may affect repolarization and alter
the repolarization reserve, leading to the development of arrhythmias. Pharmacological enhancement of
outward currents or suppression of inward currents has been shown to be of therapeutic value. A number
of newly found selective ion channel inhibitors or agonists have been investigated for their ability to
enhance repolarization reserve and decrease the incidence of arrhythmia. In this paper we review the
development, potential mechanisms, clinical application, and pharmacological significance of repolarization reserve in order to better understand, predict and prevent unexplained adverse cardiac events.
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E-mail address: [email protected] (Yang Li).
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http://dx.doi.org/10.1016/j.apsb.2013.03.001
Repolarization reserve, arrhythmia and new drug development
1.
Introduction
Enhanced variability in cardiac repolarization has been linked to
increased arrhythmic risk in both experimental and clinical studies.
Clinicians have found that some drugs producing minimal QT
prolongation in one patient may cause significant QT prolongation
or torsade de pointes (TdP) in the other patients1. The causes of
spatio-temporal cardiac repolarization variability are still under
investigation. The term “repolarization reserve” was first raised by
Roden in 19982. After 10 years, repolarization reserve has been
defined by Roden again as following3: “Loss of one component
(such as rapidly delayed rectified potassium currents, IKr) ordinarily will not lead to failure of repolarization (i.e., marked QT
prolongation); as a corollary, individuals with subclinical lesions
in other components of the system, say slowly delayed rectified
potassium currents (IKs) or calcium current, may display no QT
change until IKr block is superimposed.” This suggests that other
Kþ currents are compensatorily increased when dysfunction or
inhibition of one Kþ current occurs, so that changes in action
potential duration (APD) are minimized. It has proposed that
pathologic factors contributing to dysfunction of repolarization
reserve would bring not only excessive APD prolongation but
lethal arrhythmias by mild blockade of potassium channels4. The
repolarization reserve concept seems to be a new approach for
clinicians to better understand adverse drug reactions, cardiac
repolarization and arrhythmias.
2.
Ion mechanism of repolarization reserve
It is thought that subtle interactions of multiple ion channels
govern the repolarization process of cardiac myocytes. A major
mechanism contributing to repolarization reserve is IKr and IKs. At
the ionic level, IKs is an important determinant of ventricular
repolarization. Although IKs may have little role in APD under
physiologic conditions, it probably plays a vital role when APD is
abnormally prolonged by reduction of outward currents or
enhancement of inward currents induced by drug usage, hypokalaemia, genetic abnormality and bradycardia5. The subsequent
prolongation in APD would result in IKs activation and exert
negative feedback to further APD prolongation. IKr is not only a
main outward current determining repolarization but itself is
clearly the most important contributor to repolarization reserve.
Studies have demonstrated that reductions in IKr may lead to
compensatory up-regulation of IKs. Xiao et al.6 reported that adult
canine left ventricular cardiomyocytes treated with dofetilide for
24 h developed APD shortening and enhancement of repolarization reserve, which was accompanied by increased IKs density.
Dofetilide had no significant effect on mRNA expression corresponding to KCNH2 (potassium voltage-gated channel subfamily
H member 2) and KCNE2 (potassium voltage-gated channel
subfamily E member 2) for IKr or KCNQ1 (potassium voltagegated channel KQT-like subfamily member 1) and KCNE1 for IKs,
but increased protein expression of KvLQT1 and KCNE1. The
expression levels of the muscle-specific microRNA subtypes miR133a and miR-133b were significantly reduced in the dofetilide
group compared with the control group, suggesting that the
compensatory upregulation of IKs was achieved through posttranscriptional regulation, and was closely associated with microRNA
changes. IKs gating mechanisms responsible for the change of
repolarization reserve is gradually becoming elucidated. The
closed states of the gating channel play a key role in IKs current
151
change. In 2003, Silverman provided a hypothesis that IKs has two
closed states. The second closed state must arise from first state
via a slow transition phase7. It is recognized that 40% of the
channels were in first closed state at low heart rates and 60% of the
channels were in first closed state at high heart rates. At high heart
rates, more first-closed channels contribute to repolarizing reserve.
IKs has a reserve of channels in the closed state that can open
rapidly to generate current at fast rate (rate-adaptation), preventing
excessive APD prolongation and proarrhythmia6,8.
It recently has been reported that other currents also contribute to
repolarization reserve. Several studies indicated that late sodium
current (INa,L) was up-regulated by various factors and represented a
functional reserve under disease conditions. Augmentation of INa,L
by gene mutations or polymorphisms and drugs opposes outward
currents and impairs repolarization reserve. Enhancement of INa,L
has been shown to elicit delayed after-depolarization and induce
long QT3(LQT3) syndrome and other arrhythmias. Studies showed
that drug-induced reduction of INa,L in cardiomyocytes isolated
from ischemic myocardium exposed to oxidative stress is closely
related to cardiac electrical activity9,10.
Surprisingly and interestingly, the hyperpolarization activity
current (If), which contributes to the pacemaker current in the sinus
node, also affects repolarization reserve. Hofmann et al.11 reported
the notable increase of HCN1 (potassium/sodium hyperpolarizationactivated cyclic nucleotide-gated channel 1) in the hypertrophic
ventricle, while low levels of HCN1 are expressed under normal
physiological conditions. HCN channel activity, as an inward
current, can contribute to action potential repolarization. Moreover,
blockade of ventricular HCN current by drugs improves the
repolarization reserve and helps to maintain electrical stability in
cardiac disease states, as evidenced by the beneficial effect of the Ifblock erivabradine on heart failure12.
The inward sarcolemmal NCX current might significantly
reduce the function of repolarization reserve in calcium overloads
and induce early (EADs) and delayed after-depolarization
(DADs). Consequently, the vulnerability to arrhythmias is
increased13. SEA0400, with its acute inhibition of NCX, prevents
polymorphic VTs in experimental models of long QT2 (LQT2)
syndrome and LQT3, improving repolarization reserve and reducing the burden of proarrhythmia14.
3.
Repolarization reserve and arrhythmias
To better understand the relationship between repolarization
reserve and arrhythmias, a unifying framework for understanding
their relationship to cardiac repolarization is provided15. Inherited
arrhythmias result from mutations in genes encoding cardiac ion
channels, cytoskeletal anchoring proteins and components of
caveolae. In contrast, acquired arrhythmias are induced through
blockade of IKr by many cardiac and non-cardiac drugs. Other risk
factors that may contribute to ionic disturbances include gender
and cardiac pathology. The interplay of the above factors
determines the repolarization reserve capacity. Attenuation of the
repolarization reserve due to drugs, remodeling, or genetic
disorders may lead to prolonged repolarization and development
of lethal arrhythmia under certain conditions.
In the clinical setting, reduction of repolarization reserve has
been associated with an increased risk of arrhythmogenesis in
patients with inherited LQTs and/or structural heart disease.
Repolarization reserve might be further diminished by concomitant drug therapy and a variety of conditions such as hypokalemia
152
and bradycardia. Electrophysiological remodeling of ion channels
in heart failure leads to prolongation of APD and decreased
repolarization reserve, incorporating down-regulated IKs and upregulated INCX and INa,L13,16. Excessive prolongation of APD and
impairment of repolarization reserve will lead to arrhythmogenic
after-depolarizations, especially EADs, with triggering complex
re-entry. Guo et al.17 found by pharmacologic manipulation that
IKs becomes the main repolarization current rather than IKr in early
reperfusion. A drug-induced blockade of IKs in this situation led to
an increase in ventricular arrhythmias, which was a consequence
of impairment of the repolarization reserve.
The mechanism by which impairment of repolarization reserve
develops into arrhythmia is still masked. According to a theory
introduced by Varró18, lengthening of repolarization and
decreased repolarization reserve lead to enhanced spatial repolarization heterogeneity. This hypothetical mechanism suggests that
the effective refractory period (ERP) is significantly shorter than
the APD in normal conditions. The cells are resistant to early
stimulation because they are in a refractory state. However, in
pathologic circumstances, ERP is prolonged and the repolarization
heterogeneity is augmented by repolarization reserve impairment.
Consequently, a premature beat stimulus can travel back to its
origin due to enhanced differences in refractoriness of different
heart regions, leading to ventricular arrhythmias. According to this
concept, distribution in mid-myocardium of IKs is much less than
in the epicardium, which likely leads to a greater prolongation of
APD in the mid-myocardium by the IKs blocker, thereby increasing transmural repolarization-dispersion (TRD) and inducing
arrhythmias. In contrast, a greater distribution of INa in endocardial
rather than epicardial tissue allows a greater prolongation of ERP
in the endocardium by the INa blocker and reduces ERP dispersion, exerting an antiarrhythmic effect.
4. Repolarization reserve and new drug development
strategy
Unexpected induction of arrhythmias in the heart is still one of the
major risks of new drugs despite recent improvements in cardiac
safety assays. The major adverse effects of drugs have been
associated with decreased cardiac repolarization reserve. The
drugs may not cause significant APD lengthening under normal
conditions, but in patients with impaired repolarization reserve, the
risk for excessive APD prolongation and arrhythmia are greatly
enhanced. Therefore, the preclinical safety pharmacology screenings should be extended to preparations in which repolarization
reserve is modified. Therapeutically, there are several basic
options to enhance repolarization reserve and decrease the risk
of proarrhythmia. Firstly, it would be beneficial to inhibit inward
sodium and calcium currents, and to increase more than one
outward potassium currents would also be advisable, which is
expected to have much less proarrhythmic risk than selective
potassium channel inhibitors. The best candidate in this case is
amiodarone. As one of the most effective selective potassium
channels blockers, amiodarone also inhibits both INa and ICa,L,
substantially lengthening repolarization. Its proarrhythmic effect is
consequently much less significant than other class III antiarrhythmics which inhibit only potassium channels19. Recently,
dronedarone, a modified analogue of amiodarone which inhibits
Naþ, Ca2þ and NCH4 channels, has drawn great attention for its
ability to maintain sinus rhythm and terminate a trial fibrillation20.
Vernakalant may affect several ion channels expressed in atrium
Yang Li, Yicheng Fu
myocytes and protect against Naþ channel blockade21. Secondly,
as a negative feedback mechanism, enhancement of Kþ currents
would limit repolarization prolongaton. A recent study on repolarization reserve indicated that pharmacological activation of IKs
enhances antiarrhythmic characteristics and counteracts IKr reduction6. The benzodiazepine L-364,373(R-L3) stimulates IKs activation, compensates for repolarization impairment due to reduced
IKr, and decreases QT variability and the occurrence of extrasystoles in the heart failure22. hERG channel agonists, NS-3623
and NS-1643, were found to enhance IKr and limit QT prolongation in experimental animal models23,24. ATP-sensitive potassium
channel (KATP) openers, nicorandil, pinacidil and diazoxide,
suppress EADs and decrease the incidence of premature ventricular contractions25,26. SNC-80, selectively activating the deltaopioid receptor, subsequently opens KATP channels and provides
cytoprotection and antiarrhythmic protection against hypoxia
reoxygenation effects27. Lastly, the development of new drug
should evaluate their effect on repolarization heterogeneity.
Studies indicate that impairment in repolarization reserve elicits
TdP by increasing repolarization heterogeneity and triggered
activity28. The difference between the APD and the ERP of
adjacent cells is very small under normal conditions. However,
repolarization heterogeneities would be amplified and repolarization reserve would be reduced with the usage of pro-arrhythmic
cardiac and non-cardiac drugs under pathologic conditions, which
could dramatically increase the incidence of lethal arrhythmias18.
As a new concept, repolarization reserve explains the interaction of multiple currents contributing to cardiac reserve function.
Accordingly, inhibition or functional impairment of one ion
channel does not lead to prolongation of repolarization owing to
compensation from other currents. Currently, most research on
mechanisms of repolarization reserve use only isolated cardiomyocytes. The cardiac action potential represents the integrated
activity of dozens or hundreds of individual components of ion
currents, and the behavior of these individual components
generates and affects the action potential. Future research should
be directed at providing a framework for the interaction of ion
currents and the generation of repolarization reserve.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (No. 81170177).
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